DETERMINATION OF THE CONFORMATION OF FOLDING INITIATION SITES IN PROTEINS BY COMPUTER-SIMULATION

Experimental evidence and theoretical models both suggest that protein folding begins by specific short regions of the polypeptide chain int ermittently assuming conformations close to their final ones. The inde pendent folding properties and small size of these folding initiation sites make them suitable subjects for computational methods aimed at d eriving structure from sequence. We have used a torsion space Monte Ca rlo procedure together with an all-atom free energy function to invest igate the folding of a set of such sites. The free energy function is derived by a potential of mean force analysis of experimental protein structures. The most important contributions to the total free energy are the local main chain electrostatics, main chain hydrogen bonds, an d the burial of nonpolar area. Six proposed independent folding units and four control peptides 11-14 residues long have been investigated. Thirty Monte Carlo simulations were performed on each peptide, startin g from different random conformations. Five of the six folding units a dopted conformations close to the experimental ones in some of the run s. None of the controls did so, as expected. The generated conformatio ns which are close to the experimental ones have among the lowest free energies encountered, although some less native like low free energy conformations were also found. The effectiveness of the method on thes e peptides, which have a wide variety of experimental conformations, i s encouraging in two ways: First, it provides independent evidence tha t these regions of the sequences are able to adopt native like conform ations early in folding, and therefore are most probably key component s of the folding pathways. Second, it demonstrates that available simu lation methods and free energy functions are able to produce reasonabl y accurate structures. Extensions of the methods to the folding of lar ger portions of proteins are suggested. (C) 1995 Wiley-Liss, Inc.